Multiple unit dosage form having a therapeutic agent in combination with a nutritional supplement

ABSTRACT

Compositions and methods for combination therapy are provided. The compositions comprise a multiple unit dosage form having both a therapeutic agent and a nutritional supplement. The combination therapy is useful for restoring a nutrient depletion associated with a particular disease state. Additionally, the combination therapy can prevent or attenuate the depletion of a nutrient caused, in whole or in part, by the co-administrated therapeutic drug. Methods of manufacturing the formulations are likewise described.

RELATED APPLICATIONS

The present application is a continuation of PCT/US2008/067736, filedJun. 20, 2008, which designated the United States and was published inEnglish, which claims priority under 35 U.S.C. §119(e) to U.S.Provisional Application Ser. No. 60/946,357, filed on Jun. 26, 2007, byJames R. Komorowski, entitled “MULTIPLE UNIT DOSAGE FORM HAVING ATHERAPEUTIC AGENT IN COMBINATION WITH A NUTRITIONAL SUPPLEMENT.” Thecontent of each of these applications is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a formulation and treatment regime thatprovides to a patient, in a single dosage form, a combination of atherapeutic drug and a nutritional component. More particularly, theinvention provides a multiple unit dosage form having a therapeuticcomponent and a nutritional and/or vitamin component, wherein thetherapeutic agent is intended for the treatment of a disease or medicalcondition and the nutritional component is beneficial to the patient forthe same disease condition, or a related disease condition.Alternatively, the nutritional component serves to compensate for arelative or frank nutrient deficiency caused by the disease to betreated or by the therapeutic agent. Additionally, a method for themanufacture of such a formulation and the use of the formulation for thetreatment of various diseases and conditions are likewise provided.

2. Description of the Related Art

Over the past several decades, ample evidence documents that majorportions of various subgroups of individuals stratified by age, gender,socioeconomic status, and disease states, cannot meet the RecommendedDietary Allowances (RDAs) of foods containing essential compounds andelements, including specific vitamins and minerals such as calcium,potassium, iron, iodine, zinc, vitamin B12, vitamin B6, vitamin E,magnesium, folic acid, copper, selenium, and chromium. Thus, vitamin andmineral supplementation has become a recognized method of meetingacceptable medical and public health nutrition standards. Research hassuggested that antioxidant micronutrients are involved in preventingmolecular biological processes affecting health and disease at thesubcellular and submolecular level. Specific vitamins and minerals havebeen shown to advance immune system integrity, moderate the agingprocess, and play a role in the prevention of atherosclerosis andcancer.

Vitamin and mineral preparations are commonly administered to treatspecific medical conditions or as general nutritional supplements.Recent studies have elucidated the important physiological roles playedby vitamins and minerals, and established a correlation betweendeficiencies or excesses of these nutrients and the etiologies ofcertain disease states in humans. See, e.g., Diplock, “AntioxidantNutrients and Disease Prevention: An Overview,” Am. J. Clin. Nutr.,53:189-193 (1991); Document Geigy Scientific Tables, 457-497 (Diem andCemtuer eds., 7th ed., 1975).

Numerous diseases and medical conditions are caused or exacerbated byvitamin or nutritional deficiencies. Moreover, various therapeutictreatment regimes have been associated with vitamin depletion. It wouldtherefore be desirable to provide improved therapeutics which obviatethe deficiencies of known therapeutic agents while satisfying the longstanding need for such therapeutic agents.

SUMMARY OF THE INVENTION

The invention disclosed herein includes a multiple unit dosage form fororal administration comprising an effective amount of a therapeuticagent, a barrier layer, and a nutritional supplement, wherein thetherapeutic agent and the nutritional supplement are formulated as asingle dose. In certain aspects of the invention, the barrier layer islocated between the therapeutic agent and the nutritional supplement andprevents interaction between said therapeutic agent and said nutritionalsupplement. Advantageously, the barrier layer is comprised of acontrolled-release, delayed-release, or enteric coating.

The therapeutic agent can be any of a variety of agents which includeantidepressants, anti-thombotics, anti-diabetics, anti-psychotics, andstatin drugs. The nutritional supplement may be a vitamin, a mineral, anessential metal, and/or a co-enzyme. Advantageously, the dosage form isa tablet, a capsule, a gel cap, or a caplet.

In an aspect of the invention, the dosage form includes a coating on theexterior of which controls the release of the therapeutic agent and thenutritional supplement.

In another aspect of the invention, the therapeutic agent is optionallya statin drug and the nutritional supplement is co-enzyme Q10.Alternatively, the therapeutic agent may be warfarin and the nutritionalsupplement may be magnesium taurate. Similarly, the therapeutic agentmay be sulphonylurea and the nutritionally supplement is a chromiumcomplex. The therapeutic agent may be zidovudine and the nutritionalsupplement may be selenium.

When the nutritional supplement is a chromium complex, the chromiumcomplex may be chromium polynicotinate, chromium picolinate, chromiumacetate, chromium histidinate, chromium nicotinate, chromium chloride,or a chromium yeast.

In some aspects, the therapeutic agent is metformin and the nutritionalsupplement is a chromium complex. However, the therapeutic agent may beglipizide or olanzapine. The dosage form may additionally include apharmaceutically acceptable carrier.

In still another aspect of the invention, the dosage form ischaracterized as having the therapeutic agent located at the center ofthe form and the nutritional supplement located at the outer portion ofthe form. Advantageously, the barrier layer separates the therapeuticagent from the nutritional supplement. Alternatively, the nutritionalsupplement may be located at the center of the form and the therapeuticagent may be located at the outer portion of the form. Again, thebarrier layer separates the nutritional supplement from the therapeuticagent.

A method of restoring nutritional depletion related to a disease stateis likewise provided. The method includes administering to a patient inneed thereof a multiple unit dosage form for oral administrationcomprising an effective amount of a therapeutic agent, a barrier layer,and a nutritional supplement, wherein the therapeutic agent and thenutritional supplement are formulated as a single dose.

A method of preventing and/or attenuating depletion of a nutrient causedby the co-administration of a therapeutic agent to an individual in needthereof is also disclosed. The method includes identifying an individualpresenting with nutrient depletion associated with the administration ofa therapeutic agent, and administering to the individual a multiple unitdosage form for oral administration comprising an effective amount of atherapeutic agent, a barrier layer, and a nutritional supplement,wherein the therapeutic agent and the nutritional supplement areformulated as a single dose. The therapeutic agent may cause orexacerbate nutrient depletion and the nutritional supplement acts toprevent and/or attenuate the depletion.

A method of synergistically treating a disease or condition caused orexacerbated by nutrient depletion is similarly disclosed. The methodincludes administering to an individual in need thereof a multiple unitdosage form for oral administration comprising an effective amount of atherapeutic agent, a barrier layer, and a nutritional supplement,wherein the therapeutic agent and the nutritional supplement areformulated as a single dose.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of a tablet formulation having thetherapeutic agent disposed within the center of the tablet, anutritional supplement on the outer layer of the tablet, and middlebarrier layer separating the therapeutic drug from the nutritionalsupplement layer.

FIG. 2 is a cross sectional view of a tablet formulation having thenutritional supplement separated from the therapeutic agent by a middlebarrier layer.

FIG. 3 is a perspective view of a capsule, wherein the capsule iscomprised of therapeutic agent beadlets and nutritional supplementbeadlets.

FIG. 4 is a cross-sectional view of a gelcap having a therapeutic agentincorporated within the liquid component of the gelcap and a nutritionalsupplement incorporated within the gelatin exterior of the gelcap.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention provides a novel formulation and treatment regimeto a patient, wherein the course of therapy includes the use of in asingle dosage form having a combination of a therapeutic drug and anutritional supplement. More particularly, the invention offers amultiple unit dosage form having a therapeutic component and anutritional supplement, wherein the therapeutic agent is intended forthe treatment of a disease or medical condition and the nutritionalsupplement is beneficial to the patient for the same disease condition,or a related disease condition. As will also be described in greaterdetail below, the nutritional component can act to compensate for arelative or frank nutrient deficiency caused by the disease to betreated or by the therapeutic agent. Additionally, a method for themanufacture of such a formulation and the use of the formulation for thetreatment of various diseases and conditions are likewise provided.

The terminology used in the description presented herein is not intendedto be interpreted in any limited or restrictive manner, simply becauseit is being utilized in conjunction with a detailed description ofcertain specific embodiments described herein. Furthermore, embodimentsdescribed herein can include several novel features, no single one ofwhich is solely responsible for its desirable attributes or which isessential to practicing the invention herein described.

As used herein, the phrase “therapeutic agent” is intended to have itsbroadest possible interpretation and refers to any therapeuticallyactive substance that is delivered to a bodily conduit of a living beingto produce a desired, usually beneficial, effect. More particularly, atherapeutic agent relates to any agent that can confer a therapeuticbenefit on a patient and includes, without limitation, conventionaldrugs, gene therapy constructs, chemotherapeutic agents, antibiotics,macromolecules, and protein bound drugs. Exemplary therapeutic agentsinclude analgesics, anesthetics, anxiolytics, antidepressants such asselective serotonin reuptake inhibitors like citalopram, escitalopramoxalate, fluoxetine, fluvoxamine maleate, paroxetine, sertraline, anddapoxetine, antipsychotics including clozabine, risperidone, olanzapine,quetiapine, ziprasidone, aripiprazole, paiperidone, sertindole,zotepine, amisulpride, and melperone, and olanzapine, anticonvulsants,nervous system stimulants, antiemetics, hallucinogens, mood stabilizers,bronchodilators, decongestants, anti-proliferatives, angiotensinconverting enzyme inhibitors, antiarrhythmics, antianginals,antihypertensives, antihyperlipidemics including, for example, any of anumber of statin drugs such as atorvastatin, cerivastatin, fluvastatin,lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin,simvastatin, and ezetimibe with simvastatin, anticoagulants such aswarfarin, acenocoumarol, phenprocoumon and phenindione, antiplatelets,beta blockers, diuretics, thrombolytics, vasodilators, antacids,antidiarrheals, H2-receptor antagonists, proton pump inhibitors,laxatives, anti-inflammatories, antirheumatics, corticosteroids, musclerelaxants, anti-histamines, antibiotics, anti-virals such as ribavirin,ganciclovir, abacavir, tenofovir, vidarabine, emtricitabine, efavirenz,darunavir, delavirdine, nevirapine, protease inhibitors, lopinavir,zalcitabine, didanosine, seliciclib, chloroquine, resveratrol, andzidovudine, vaccines, anti-protozoals, anti-fungals, antihelmintics,anti-diabetics including sulfonylureas such as tolbutamide,acetohexamide, tolazamide, chlorpropamide, glipizide, glyburideglimepiride, and gliclazide, meglitinides, biguanides such as metformin,glitazones such as rosiglitazone, pioglitazone, and troglitazone, alphaglucosidase inhibitors such as miglitol and acarbose, and DPP-4inhibitors such as vildagliptin and sitagliptin, and chemotherapeuticswhich include agents such as paclitaxel, doxorubicin, and other drugswhich have been known to affect tumors. Chemotherapeutics, as usedherein, further includes agents which modulate other states which arerelated to tissues which can be permeabilized using the methods andcompositions of the invention. The chemotherapeutic agent can be, forexample, a steroid, an antibiotic, or another pharmaceuticalcomposition. Examples of chemotherapeutic agents include agents such aspaclitaxel, doxorubicin, vincristine, vinblastine, vindesine,vinorelbin, taxotere (DOCETAXEL), topotecan, camptothecin, irinotecanhydrochloride (CAMPTOSAR), doxorubicin, etoposide, mitoxantrone,daunorubicin, idarubicin, teniposide, amsacrine, epirubicin, merbarone,piroxantrone hydrochloride, 5-fluorouracil, methotrexate,6-mercaptopurine, 6-thioguanine, fludarabine phosphate, cytarabine(ARA-C), trimetrexate, gemcitabine, acivicin, alanosine, pyrazofurin,N-Phosphoracetyl-L-Asparate (PALA), pentostatin, 5-azacitidine,5-Aza-2′-deoxycytidine, adenosine arabinoside (ARA-A), cladribine,ftorafur, UFT (combination of uracil and ftorafur),5-fluoro-2′-deoxyuridine, 5-fluorouridine, 5′-deoxy-5-fluorouridine,hydroxyurea, dihydrolenchlorambucil, tiazofurin, cisplatin, carboplatin,oxaliplatin, mitomycin C, BCNU (Carmustine), melphalan, thiotepa,busulfan, chlorambucil, plicamycin, dacarbazine, ifosfamide phosphate,cyclophosphamide, nitrogen mustard, uracil mustard, pipobroman,4-ipomeanol, dihydrolenperone, spiromustine, geldanamycin,cytochalasins, depsipeptide, Lupron, ketoconazole, tamoxifen, goserelin(Zoledax), flutamide,4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluorometh-yl)propionanilide, Herceptin, anti-CD20 (Rituxan),interferon alpha, interferon beta, interferon gamma, interleukin 2,interleukin 4, interleukin 12, tumor necrosis factors, and radiation.Representative compounds used in cancer therapy further includecyclophosphamide, chlorambucil, melphalan, estramustine, iphosphamide,prednimustin, busulphan, tiottepa, carmustin, lomustine, methotrexate,azathioprine, mercaptopurine, thioguanine, cytarabine, fluorouracil,vinblastine, vincristine, vindesine, etoposide, teniposide,dactinomucin, doxorubin, dunorubicine, epirubicine, bleomycin,nitomycin, cisplatin, carboplatin, procarbazine, amacrine, mitoxantron,tamoxifen, nilutamid, and aminoglutemide. Further included within themeaning of “therapeutic agents” are immuno-suppressants, hormonalcontraceptions, selective estrogen receptor modulators, fertilityagents, and anti-pruritics. The therapeutic agent may be formulated asmicroparticles or nanoparticles. Other examples of therapeutic agentsinclude macromolecules, such as, liposomes, nanoparticles, plasmid,viral vectors, non-viral vectors, and oligonucleotides.

The phrase “nutritional supplement” is likewise intended to be affordedits broadest possible interpretation and refers to a composition that isintended to supplement the diet and bears or contains one or more of thefollowing ingredients: a vitamin, a mineral, an herb or other botanical,an essential amino acid, an essential fatty acid, a dietary substancefor use by people to supplement the diet by increasing the total dietaryintake, and a concentrate, metabolite, constituent, extract, orcombination of any of the above. Exemplary nutritional supplementsinclude, without limitation, essential fatty acids such as linolenicacid and linoleic acid, and essential amino acids such as tryptophan,lysine, methionine, phenylalanine, threonine, valine, leucine,isoleucine, arginine, and histadine. Also included within the meaning ofnutritional supplement are vitamins such as biotin (vitamin B7, vitaminH), choline (vitamin Bp), folate (folic acid, vitamin Bp, vitamin M),niacin (vitamin B3, vitamin P, vitamin PP), pantothenic acid (vitaminB5), riboflavin (vitamin B2, vitamin G), thiamine (vitamin B1), vitaminA (retinol), vitamin B6 (pyridoxine, pyridoxamine, or pyridoxal),vitamin B12 (cobalamin), vitamin C (ascorbic acid), vitamin E(tocopherol), co-enzyme Q10, and vitamin K (naphthoquinoids).Nutritional supplement further includes dietary minerals such as, forexample, chromium (including, chromium polynicotinate, chromiumpicolinate, chromium acetate, chromium histidinate, chromium nicotinate,chromium chloride, and the like, or any or any pharmaceuticallyacceptable salts, hydrates, solvates, or mixtures thereof), bromine,cobalt, copper, fluorine, germanium, iodine, iron, magnesium, manganese,molybdenum, potassium, selenium, silicon, zinc, calcium, phosphorous,sodium, sulfur, and vanadium. The amount of nutritional supplementincorporated into the multiple unit dosage form of the present inventionis quantum sufficiat to achieve the desired effect. The dosage amountsfor the disclosed nutritional supplements are well-established in thearts and can be optimized for any particular indication via routineexperimentation.

The term “patient” refers animals which can be treated using thecompositions and methods of the invention. Examples of animals includemammals, such as mice, rabbits, rats, horses, goats, dogs, cats, pigs,cattle, sheep, and primates (e.g. chimpanzees, gorillas, and,preferably, humans).

As used herein, the phrase “over a period of time,” can refer to aperiod of minutes, hours or days. For example, over a period of time canrefer to at least 10 minutes, at least 15 minutes, at least 30 minutes,at least 60 minutes, at least 75 minutes, at least 90 minutes, at least105 minutes, at least 120 minutes, at least 3 hours, at least 4 hours,at least 5 hours, at least 6 hours, at least 7 hours, at least 8 hours,at least 9 hours, at least 10 hours, at least 12 hours, at least 14hours, at least 16, hours, at least 18 hours, at least 20 hours, atleast 22 hours, at least one day, at least two days, at least threedays, at least 4 days, at least 5 days, at least 6 days, at least aweek, or any interval of time in between. In other words, the chromiumfrom the composition can be absorbed by the individual to whom it isadministered over a period of at least 10 minutes, at least 15 minutes,at least 30 minutes, at least 60 minutes, at least 75 minutes, at least90 minutes, at least 105 minutes, at least 120 minutes, at least 3hours, at least 4 hours, at least 5 hours, at least 6 hours, at least 7hours, at least 8 hours, at least 9 hours, at least 10 hours, at least12 hours, at least 14 hours, at least 16, hours, at least 18 hours, atleast 20 hours, at least 22 hours, at least one day, at least two days,at least three days, at least 4 days, at least 5 days, at least 6 days,at least a week, or any interval of time in between.

As used herein, a composition that “substantially” comprises a compoundmeans that the composition contains more than about 80% by weight, morepreferably more than about 90% by weight, even more preferably more thanabout 95% by weight, and most preferably more than about 97% by weightof the compound. As used herein, a composition that “substantially”comprises a chromium complex refers to a composition that contains morethan or equal to 7.0% of trivalent or dietary chromium. Preferably, acertificate of analysis for the compositions disclosed herein indicatethat the compositions are negative for microbial growth, yeast and moldshould be present in less than 300 cells/g and the toxic metals shouldbe less than 1 ppm.

In some embodiments, the compositions disclosed herein are in the formof pharmaceutically effective salts. The phrase “pharmaceuticallyacceptable salt(s),” is art recognized and, as used herein includes, butis not limited to, salts of acidic or basic groups that may be presentin the compositions disclosed herein. Compounds that are basic in natureare capable of forming a wide variety of salts with various inorganicand organic acids. The acids that may be used to preparepharmaceutically acceptable acid addition salts of such basic compoundsare those that form non-toxic acid addition salts, i.e., saltscontaining pharmacologically acceptable anions, including but notlimited to sulfuric, citric, maleic, acetic, oxalic, hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acidphosphate, isonicotinate, acetate, lactate, salicylate, citrate, acidcitrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentisinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds present inthe compositions disclosed herein that include an amino moiety also canform pharmaceutically acceptable salts with various amino acids, inaddition to the acids mentioned above. Compounds present in thecompositions disclosed herein that are acidic in nature are capable offorming base salts with various pharmacologically acceptable cations.Non limiting examples of such salts include alkali metal or alkalineearth metal salts and, particularly, calcium, magnesium, sodium lithium,zinc, potassium, silicon, phosphorus and iron salts.

As used herein, the term “hydrate” means a compound or a salt thereof,that further includes a stoichiometric or non-stoichiometric amount ofwater bound by non-covalent intermolecular forces. The term hydrateincludes solvates, which are stoichiometric or non-stoichiometricamounts of a solvent bound by non-covalent intermolecular forces.Preferred solvents are volatile, non-toxic, and/or acceptable foradministration to humans in trace amount.

The phrase “pharmaceutically acceptable carrier” is art recognized andincludes a pharmaceutically acceptable material, composition or vehicle,suitable for administering compounds of the present invention tomammals. The carriers include liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting the subject agent from one organ, or portion of the body,to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not injurious to the patient. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients; such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations. In oneembodiment, the pharmaceutically acceptable carrier is suitable forintravenous administration. In another embodiment, the pharmaceuticallyacceptable carrier is suitable for locoregional injection.

The term “pharmaceutically acceptable esters” refers to the relativelynon-toxic, esterified products of the compounds of the presentinvention. These esters can be prepared in situ during the finalisolation and purification of the compounds, or by separately reactingthe purified compound in its free acid form or hydroxyl with a suitableesterifying agent. Carboxylic acids can be converted-into esters viatreatment with an alcohol in the presence of a catalyst. Hydroxyls canbe converted into esters via treatment with an esterifying agent such asalkanoyl halides. The term also includes lower hydrocarbon groupscapable of being solvated under physiological conditions, e.g., alkylesters, methyl, ethyl and propyl esters. (See, for example, Berge etal., supra.)

The language “pharmaceutical composition” is used interchangeably with“therapeutic agent” and includes preparations suitable foradministration to mammals, e.g., humans. When the compounds of thepresent invention are administered as pharmaceuticals to mammals, e.g.,humans, they can be given per se or as a pharmaceutical compositioncontaining, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) ofactive ingredient in combination with a pharmaceutically acceptablecarrier. The amount of therapeutic agent incorporated into the multipleunit dosage form of the present invention is quantum sufficiat toachieve the desired therapeutic effect. The dosage amounts for thedisclosed therapeutic agents are well-established in the arts and can beoptimized for any particular indication via routine experimentation.

Turning more particularly to the disclosed invention, one object of thepresent invention is to provide a pharmaceutical multiple unit dosageform comprising both a therapeutic agent and a nutritional supplement,wherein the therapeutic agent and the nutritional supplement areco-formulated such that the therapeutic agent is contained in the centeror core of the tablet, capsule, or gel cap and the nutritionalsupplement is contained on the outer portion of the tablet, capsule, orgel cap as illustrated in FIG. 1. FIG. 1 is a cross sectional view of atablet formulation, wherein the therapeutic agent is disposed within thecenter of the tablet and the nutritional supplement is located on theouter layer of the tablet. Also illustrated is a middle barrier layer,which separates the therapeutic drug from the nutritional supplementlayer. The middle barrier layer will be described in greater detailbelow. In an alternative embodiment, the therapeutic agent is formulatedsuch that it is contained in the outer coating or outer portion of thetablet, capsule, or gel cap and the nutritional supplement is formulatedat the center or core of the tablet, capsule or gel cap. In stillanother embodiment, the nutritional supplement and therapeutic agent areboth in the center of the tablet but the two components are separated bya middle barrier layer as illustrated in FIG. 2.

As will be described in greater detail below, the formulation of thepresent invention includes both a nutritional supplement and atherapeutic agent for oral administration. The formulation disclosedherein can be provided as a tablet, aqueous or oil suspension,dispersible powder or granule, emulsion, hard or soft capsule, syrup,elixir, or beverage. Compositions intended for oral use can be preparedaccording to any method known in the art for the manufacture ofpharmaceutically acceptable compositions and such compositions maycontain one or more of the following agents: sweeteners, flavoringagents, coloring agents and preservatives. The sweetening and flavoringagents will increase the palatability of the preparation. Tabletscontaining chromium complexes in admixture with non-toxicpharmaceutically acceptable excipients suitable for tablet manufactureare acceptable. Pharmaceutically acceptable vehicles such as excipientsare compatible with the other ingredients of the formulation (as well asnon-injurious to the patient). Such excipients include inert diluentssuch as calcium carbonate, sodium carbonate, lactose, calcium phosphateor sodium phosphate; granulating and disintegrating agents, such as cornstarch or alginic acid; binding agents such as starch, gelatin oracacia; and lubricating agents such as magnesium stearate, stearic acidor talc. Tablets can be uncoated or can be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period of time. Forexample, a time delay material such as glyceryl monostearate or glyceryldistearate alone or with a wax can be employed. The tablet, capsule, gelcap or caplet is manufactured by a standard process, for example, in thecase of tablet, direct compression or a wet or dry granulation process.

In some embodiments, the compositions disclosed herein are formulatedfor oral delivery, for example in the form of tablets, lozenges, aqueousor oily suspensions, granules, powders, emulsions, capsules, syrups, orelixirs. Compounds and compositions described herein for oral deliverycan also be formulated in foods and food mixes. Orally administeredcompositions can contain one or more optionally agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry; coloringagents; and preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, when in tablet or pill form, the compositions canbe coated to delay disintegration and absorption in the gastrointestinaltract thereby providing a sustained action over an extended period oftime. Selectively permeable membranes surrounding an osmotically activedriving compound are also suitable for orally administered compounds andcompositions described herein. In these later platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard vehicles such as mannitol, lactose, starch, magnesium stearate,sodium saccharine, cellulose, magnesium carbonate, etc. Such vehiclesare preferably of pharmaceutical grade.

The nutritional supplement and therapeutic agent, pharmaceuticallyacceptable salts of the therapeutic agent, and pharmaceuticallyacceptable solvates of the therapeutic agent can be co-formulated alonebut, in human therapy, will generally be administered in admixture witha suitable pharmaceutical excipient diluent or carrier selected withregard to the intended route of administration and standardpharmaceutical practice. For example, the combination therapy comprisinga therapeutic agent and a nutritional supplement can be administeredorally, buccally or sublingually in the form of tablets, capsules(including soft gel capsules), ovules, elixirs, solutions orsuspensions, which may contain flavoring or coloring agents, forimmediate-, delayed-, modified-, sustained-, or controlled-releasedelivery applications. Modified release dosage forms can containexcipients such as those detailed for immediate release dosage formstogether with additional excipients that act as release rate modifiers,these being coated on and/or included in the body of the device. Releaserate modifiers include, but are not exclusively limited to,hydroxypropylmethyl cellulose, methyl cellulose, sodiumcarboxymethylcellulose, ethyl cellulose, cellulose acetate, polyethyleneoxide, Xanthan gum, Carbomer, ammonio methacrylate copolymer,hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetatephthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acidcopolymer and mixtures thereof. Modified release release dosage formsmay contain one or a combination of release rate modifying excipients.Release rate modifying excipients can be present both within the dosageform i.e. within the matrix, and/or on the dosage form i.e. upon thesurface or coating.

The tablet, capsule, gel cap, or caplet can contain excipients such asmicrocrystalline cellulose, lactose, sodium citrate, calcium carbonate,dibasic calcium phosphate and glycine, disintegrants such as starch(preferably corn, potato or tapioca starch), sodium starch glycollate,croscarmellose sodium and certain complex silicates, and granulationbinders such as polyvinylpyrrolidone, hydroxypropylmethyl cellulose(HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia.Additionally, lubricating agents such as magnesium stearate, stearicacid, glyceryl behenate and talc can also be included. In addition tothe therapeutic and nutritional supplement components of the multipleunit dosage form, the active substances can be mixed with additionalcomponents such as binders, surfactants, fillers, disintegrating agents,alkaline additives, or other pharmaceutically acceptable ingredients,alone or in mixtures. The binders are, for example, celluloses such ashydroxypropyl methylcellulose, hydroxypropyl cellulose, andcarboxymethyl-celluose sodium, polyvinyl pyrrolidone, sugars, starches,and other pharmaceutically acceptable substances with cohesiveproperties. In some embodiments, pharmaceutical constituents such asbinders, fillers, lubricants, distintegrating agents, surfactants, andother pharmaceutically acceptable additives are likewise incorporatedinto the formulation.

Solid compositions of a similar type can also be employed as fillers ingelatin capsules. Preferred excipients in this regard include lactose,starch, a cellulose, milk sugar or high molecular weight polyethyleneglycols. For aqueous suspensions and/or elixirs, the compounds of theinvention can be combined with various sweetening or flavoring agents,coloring matter or dyes, with emulsifying and/or suspending agents andwith diluents such as water, ethanol, propylene glycol and glycerin, andcombinations thereof.

The compound of the invention may also be administered via fastdispersing or fast dissolving dosages forms. Fast dispersing ordissolving dosage formulations (FDDFs) may contain the followingingredients: aspartame, acesulfame potassium, citric acid,croscarmellose sodium, crospovidone, diascorbic acid, ethyl acrylate,ethyl cellulose, gelatin, hydroxypropylmethyl cellulose, magnesiumstearate, mannitol, methyl methacrylate, mint flavouring, polyethyleneglycol, fumed silica, silicon dioxide, sodium starch glycolate, sodiumstearyl fumarate, sorbitol, xylitol.

While oral administration is preferred, the multiple unit single dosageform of the invention can also be administered parenterally, forexample, intracavernosally, intravenously, intra-arterially,intraperitoneally, intrathecally, intraventricularly, intraurethrallyintrasternally, intracranially, intramuscularly or subcutaneously, or itmay be administered by infusion techniques. For such parenteraladministration, the dosage components are best used in the form of asterile aqueous solution which may contain other substances, forexample, enough salts or glucose to make the solution isotonic withblood. The aqueous solutions should be suitably buffered (preferably toa pH of from 3 to 9), if necessary. The preparation of suitableparenteral formulations under sterile conditions is readily accomplishedby standard pharmaceutical techniques well-known to those skilled in theart

In certain embodiments, the multiple unit dosage form includes at leastone middle barrier layer comprised of pharmaceutical excipients whichwould separate the therapeutic agent from the nutritional supplementcomponent. The barrier layers can be included in the formulation byart-recognized coating or layering procedures. The barrier layer iscomprised of pharmaceutically acceptable compounds such as, for example,sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol,polyvinyl acetate, hydroxypropyl cellulose, methylcellulose,ethylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulosesodium and others, used alone or in mixtures. Additives such asplasticizers, colorants, pigments, fillers, anti-tacking and anti-staticagents including magnesium stearate, titanium dioxide, talc, and otheradditives can optionally be included in the barrier layer. Without beingbound by a particular theory, it is believed that the middle barrierlayer inhibits interaction of two or more components of the therapeuticagent and nutritional supplement in the single dose form and thereby canincrease the efficacy of the therapeutic agent and/or nutritionalsupplement. In certain embodiments, the barrier layer acts as apH-buffering zone and the layer includes at least one antacid compoundselected from the group consisting of magnesium oxide, hydroxide,carbonate, aluminum or calcium hydroxide, carbonate or silicate, andcomposite aluminum/magnesium compounds. In a preferred embodiment, themiddle barrier portion is comprised of a controlled release, delayedrelease, or enteric coating to control or delay the release of the innercontents of the multiple unit dosage form. The middle layeradvantageously improves the rate of absorption of the therapeutic agentand/or nutritional supplement. In one embodiment, the middle barrierlayer increases the efficacy of the therapeutic agent and/or nutritionalsupplement.

In another embodiment, the multiple unit dosage form further includes anouter coating. The outer coating serves to provide an immediate release,controlled-release, delayed-release, or enteric-coating to control ordelay the release of the therapeutic agent and nutritional supplementcomponent. The outer coating layer (or layers) can be applied by coatingor layering procedures which are well-established in the relevant arts.The outer coating layer is at least one of a pharmaceutically acceptablecompound selected from the group consisting of sugar, polyethyleneglycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate,hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose sodium and combinationsthereof. Additives including plasticizers, colorants, pigments, fillers,anti-tacking and anti-static agents can optionally be included in theouter coating.

In preferred embodiments, the outer coating regulates release of thetherapeutic and/or nutritional supplement component from the tablet,capsule, gel cap, or caplet. Controlled-release, delayed-release, and/orenteric-coating technology is well-established in the pharmaceutical andformulation arts. It is of great advantage to both the patient and thephysician that medication be formulated so that it may be administeredin a minimum number of daily doses from which the drug is uniformlyreleased over a desired extended period of time. This effect isaccomplished using sustained or slow release compositions. Sustained orslow release compositions containing pharmaceutical medicaments or otheractive ingredients are designed to contain higher concentrations of themedicament and are prepared in such a manner as to affect sustained orslow release into the gastrointestinal digestive tract of humans oranimals over an extended period of time.

Well absorbed oral sustained or slow release therapeutic drug dosageforms have inherent advantages over conventional, immediate releasedosage forms. The advantages include less frequent dosing of amedicament and resultant patient regime compliance, a more sustaineddrug blood level response, therapeutic action with less ingested drugand the mitigation of side effects. By providing a slow and steadyrelease of the medicament over time, absorbed drug concentration spikesare mitigated or eliminated by affecting a smoother and more sustainedblood level response.

Various hydrophilic and hydrophobic materials, including polymers, canbe utilized in preparing sustained release formulations. Theseformulations are prepared by various methods well-established in thetableting arts, such as solvent evaporation, heat melting, directcompression and wet granulation. In some embodiments, waxes and lipidsare used as coating material to retard the release of drugs. The commonmethods of manufacturing sustained release medicaments in oral dosageforms using waxes as the controlled release material admixed with themedicament are (a) melting the drug and wax together, then cooling andmilling the melt, and finally tableting after mixing with excipient; (b)using wet granulation techniques, employing an organic solvent as agranulating medium; (c) mixing the drug and waxes in a high shearmixture and using the heat produced during the processing to achieve ahomogenous mixture; and (d) using heat radiation to effect melting ofthe wax in the presence of the drug.

In one embodiment of the invention, controlled release coatings areprepared by forming a matrix by entrapping the therapeutic agent and/ornutritional supplement in excipients. Diffusion and/or erosion operateto release the active therapeutic and/or nutritional supplementsubstance depending on the properties of the active agent and thepolymer incorporated in the formulation. One particular attempt atcontrolled release is detailed in European Patent publication 0 593 309A2 to Columbo, hereby incorporated by reference in its entirety. Thepublication shows a three-layer system consisting of two externalswelling layers separated by an interposed soluble layer, and atwo-layer system consisting of a swellable layer adjacent a solubleand/or erodible layer. The swellable layer(s) consist of methylcellulose, carboxymethylcellulose sodium, crosslinkedcarboxymethylcellulose sodium, crosslinked hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethyl starch, polymethacrylate,polyvinylpyrrolidone, polyvinyl alcohols, polyethylene glycols, orpotassium methacrylate-divinyl benzene copolymer and mixtures thereof.

The soluble and/or erodible layer includes hydroxyethylcellulose,carboxymethylcellulose, alginates, albumin, soluble starch and/orgelatin, mixed with at least one soluble excipient such as saccharideand polyalcohol. In one embodiment, the swellable layer(s) contain anactive therapeutic agent. As the swellable layers swell and the erodiblelayer erodes, the therapeutic agent is released from the swellablelayers. In another embodiment, the swellable layer(s) contain anutritional supplement. In yet another embodiment, the swellablelayer(s) contain both the active therapeutic agent and the nutritionalsupplement.

In certain embodiments, the multiple unit dosage form of the presentinvention includes an enteric coating layer. The enteric coatinglayer(s) are applied using a suitable coating technique. The entericcoating layer material can be dispersed or dissolved in either water orin suitable organic solvents. As enteric coating layer polymers one ormore, separately or in combination, of the following can be used; e.g.solutions or dispersions of methacrylic acid copolymers, celluloseacetate phthalate, hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate succinate, polyvinyl acetatephthalate, cellulose acetate trimellitate, carboxymethylethylcellulose,shellac or other suitable enteric coating layer polymer(s). The entericcoating layers contain pharmaceutically acceptable plasticizers toobtain the desired mechanical properties such as flexibility andhardness of the enteric coating layers. Such plasticizers are, forinstance, but not restricted to, triacetin, citric acid esters, phthalicacid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols,polysorbates or other plasticizers. The amount of plasticizer isoptimized for each enteric coating layer formula in relation to selectedenteric coating layer polymer(s), selected plasticizer(s) and theapplied amount of the polymer(s), in such a way that the mechanicalproperties such as flexibility and hardness of the enteric coatinglayers, are adjusted so that the acid resistance of the formulation doesnot decrease significantly during the compression of the components intotablets, for example. The amount of plasticizer is usually above 10% byweight of the enteric coating layer polymer(s), preferably 15-50%, andmore preferably 20-50%. Additives such as dispersants, colorants,pigments, polymers, anti-tacking and anti-foaming agents can likewise beincluded into the enteric coating layer(s). In some embodiments, othercompounds can be added to increase film thickness and to decreasediffusion.

The present invention further includes a single dose form having atherapeutic agent and a nutritional supplement in a capsule. Capsuleformulation is well-established in the pharmacological arts. See, e.g.,U.S. Pat. No. 3,965,256 to Leslie, the entire contents of which arehereby incorporated by reference. Slow release capsules are prepared byfilling the appropriate quantity of the above described tabletgranulation mixture into gelatin capsules of suitable size and shape,with slight modification such as, for example, eliminating the tabletlubricant or the tablet binder. A slow release capsule may contain themixture of the appropriate quantity of the combination of higheraliphatic alcohol and hydrated hydroxy-alkyl cellulose together with theactive ingredients (a therapeutic agent and a nutritional supplement)and diluent. The diluent serves to achieve the appropriate concentrationof the slow release composition within the unit dosage form. As for theslow release tablet preparations, the time span for the release of theactive ingredient in the capsule formulation will depend upon theconcentration of the slow release composition within the total weight ofthe capsule formulation.

Formulations for oral use can be presented as hard gelatin capsuleswherein the active ingredients (i.e., the therapeutic agent and thenutritional supplement) are mixed with an inert solid diluent, forexample calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, such as peanut oil, liquid paraffin or olive oil. Aqueoussuspensions can contain the chromium complex of the invention inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include suspending agents, dispersing orwetting agents, one or more preservatives, one or more coloring agents,one or more flavoring agents and one or more sweetening agents such assucrose or saccharin.

When the multiple unit single dose form of the present invention isformulated as a capsule, the therapeutic agent and nutritionalsupplement are, in certain embodiments, formulated in microcapsules orbeadlets, wherein the therapeutic agent and the nutritional supplementare contained in separate microcapsules or beadlets as illustrated inFIG. 3. Preferably, the microcapsules or beadlets are protected by anouter coating as described above with reference to tablet formulations.

In another embodiment, the multiple unit single dose form is formulatedas a softgel capsule, wherein the therapeutic agent is located withinthe center of the capsule in liquid or semi-liquid form and thenutritional supplement is integrated into the outer layer of the capsuleas illustrated in FIG. 4. In an alternate embodiment, the softgelcapsule includes the nutritional supplement within the center of thecapsule in liquid or semi-liquid form and the therapeutic agent isincorporated within the outer layer of the capsule. Oil suspensions canbe formulated by suspending the active ingredient in a vegetable oil,such as arachis oil, olive oil, sesame oil or coconut oil, or in amineral oil such as liquid paraffin. The oil suspension can contain athickening agent, such as beeswax, hard paraffin or cetyl alcohol.Sweetening agents, such as those set forth above, and flavoring agentscan be added to provide a palatable oral preparation. These compositionscan be preserved by an added antioxidant such as ascorbic acid.Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Additional excipients,for example sweetening, flavoring and coloring agents, can also bepresent.

Syrups and elixirs can be formulated with sweetening agents, such asglycerol, sorbitol or sucrose. Such formulations can also contain ademulcent, a preservative, a flavoring or a coloring agent.

It will be appreciated by the skilled artisan that the amount oftherapeutic agent in combination with nutritional supplement that can becombined with the carrier material to produce a single dosage form willvary depending upon the host treated and the particular mode ofadministration.

When administered to a mammal, e.g., to an animal for veterinary use orfor improvement of livestock, or to a human for therapeutic use, thecompositions disclosed herein are administered in isolated form or asthe isolated form in a therapeutic composition. As used herein,“isolated” means that the compositions disclosed herein are separatedfrom other components of either (a) a natural source, such as a plant orcell or food, preferably bacterial culture, or (b) a synthetic organicchemical reaction mixture. Preferably, via conventional techniques, thecompositions disclosed herein are purified. As used herein, “purified”means that when isolated, the isolate contains at least 95%, preferablyat least 98% of the composition.

Compositions and methods for restoring a nutrient depletion related to aparticular disease state are likewise disclosed. The present inventionis based, in part, on the surprising discovery that a compositioncomprising both a nutritional supplement and a therapeutic agent can beadministered as a single unit dose form, wherein the therapeutic agenttreats a disease or medical condition and the nutritional supplementcomponent addresses the nutritional deficiencies associated with thatsame disease or condition. For example, a dietary magnesium (Mg)deficiency is often associated with cardiovascular disease and/orstroke. Mg deficiency can cause cardiovascular lesions leading todisease at all stages of life. Otherwise normal, Mg deficient dietscause arterial and myocardial lesions in all animals, and diets that areatherogenic, thrombogenic and cardiovasopathic, as well as Mg-deficient,intensify the cardiovascular lesions, whereas Mg supplementationprevents them. Diuretics and digitalis can intensify an underlying Mgdeficiency, leading to cardiac arrhythmias that are refractory unless Mgis added to the regimen. A composition comprising an anti-thromboticsuch as warfarin or Plavix® and magnesium taurate, for example, canaddress both the underlying disease as well as the nutrient depletionrelated to the cardiovascular disease state. Similarly, in HIV/AIDSpatients, a depletion of selenium has been observed and can result incardiomyopathy. The administration of a composition comprising bothselenium and an HIV/AIDS drug, e.g. zidovudine, would supplement thedearth of nutritional selenium and treat the symptoms of the underlyingviral infection. In certain embodiments, the compositions disclosedherein are provided to a subject, such as a mammal, as a preventativemeasure against such diseases. As used herein, “prevention” or“preventing” refers to a reduction of the risk of acquiring a givendisease or disorder alone or in combination with other clinicalcondition. A tablet comprising selenium and zidovudine, for example, cannot only treat selenium depletion associated with HIV/AIDS but alsoprevent the depletion of selenium in an individual identified with thedisease but not yet exhibiting symptoms of selenium depletion.

Compositions and methods for addressing nutrient depletion caused by atherapeutic drug regime are likewise provided. Various therapeuticinterventions have been shown to deplete nutrients in individuals beingtreated with certain pharmaceutical drugs. For example, statin drugs, orHMG-CoA reductase inhibitors, are a class of drugs used to lowercholesterol. Statins work by inhibiting the enzyme HMG-CoA reductase,the enzyme that determines the rate of cholesterol formation. Someresearch suggests that statin drugs may interfere with the body'sproduction of co-enzyme Q10 (Co q10), a substance produced naturally inthe body and found in every cell. Co q10 has a key role in themitochondria, the part of a cell that produces energy. Statins have beenfound to decrease Co q10 production as a side effect of their action. AColumbia University study in New York found that 30 days of statintherapy (80 mg/day) decreased Co q10 levels by half. Another study byresearchers at Kanazawa University in Japan found that smaller doses ofstatin drugs can reduce Co q10. After 8 weeks of 10 mg a day statintherapy, Co q10 levels decreased by 40 percent. Some researchers havetherefore suggested that this side effect may counteract any benefits oftaking statins. By providing a multiple unit single dosage formcomprising a statin drug such as lovastatin or simvastatin as thetherapeutic component and Co q10 as the nutritional supplementcomponent, the negative impact of statin drugs is greatly attenuated.The administration of a multiple unit single dosage form having Co q10as the nutritional supplement component prevents the depletion of Co q10and/or attenuates the depletion of Co q10 caused by statin drug therapy.

In yet another embodiment, compositions and methods for providing acombination therapy with a single, multiple unit tablet, capsule,caplet, or gel cap is disclosed. The nutritional supplement andtherapeutic drug act at least additively and more preferably,synergistically, to treat a disease or medical condition. One example ofsuch a combination therapy includes a tablet comprising a conventionalanti-diabetic drug such as metformin or glipizide formulated in thecenter of a tablet, a controlled release middle barrier layer whichwould act to delay the release of the therapeutic agent, and chromium onthe outer coating of the tablet. Preferably, an outer coating tofacilitate transport of chromium is included on the outermost (relativeto the center) portion of the tablet.

Dietary supplementation of chromium to normal individuals has beenreported to lead to improvements in glucose tolerance, serum lipidconcentrations, including high-density lipoprotein cholesterol, insulinand insulin binding. Anderson, 1986 Clin. Psychol. Biochem. 4:31-41.Supplemental chromium in the trivalent form, e.g. chromic chloride, isassociated with improvements of risk factors associated with adult-onset(Type 2) diabetes and cardiovascular disease. Chromium is essential foroptimal insulin activity in all known insulin-dependent systems. Boyleet al., 1977 Southern Med. J. 70:1449-1453. Insufficient dietarychromium has been linked to both maturity-onset diabetes and tocardiovascular disease.

Chromium functions as a cofactor for insulin. It binds to the insulinreceptor and potentiates many, and perhaps all, of its functions. Boyleet al., supra. These functions include, but are not limited to, theregulation of carbohydrate and lipid metabolism. Present Knowledge inNutrition, supra, at p. 573-577. The introduction of inorganic chromiumcompounds per se into individuals is not particularly beneficial.Chromium must be converted endogenously into an organic complex or mustbe consumed as a biologically active molecule. Only about 0.5% ofingested inorganic chromium, however, is assimilated into the body. Only1-2% of most organic chromium compounds are assimilated into the body.Recommended Daily Allowances, Ninth Revised Edition, The NationalAcademy of Sciences, page 160, 1980.

U.S. Pat. No. Re. 33,988 discloses that when selected essential metals,including chromium, are administered to mammals as exogenouslysynthesized coordination complexes of picolinic acid, they are directlyavailable for absorption without competition from other metals. U.S.Pat. No. Re. 33,988 describes a composition and method for selectivelysupplementing the essential metals in the human diet and forfacilitating absorption of these metals by intestinal cells. Thesecomplexes are safe, inexpensive, biocompatible, and easy to produce.These exogenously synthesized essential metal coordination complexes ofpicolinic acid (pyridine-2-carboxylic acid) have the followingstructural formula:

wherein M represents the metallic cation and n is equal to the cation'svalence. For example, when M is Cr and n=3, then the compound is chromictripicolinate. Other chromium picolinates disclosed include chromicmonopicolinate and chromic dipicolinate.

The U.S. Recommended Daily Intake (RDI) of chromium is 120 μg. U.S. Pat.No. 5,087,623, the entire contents of which are hereby expresslyincorporated herein by reference, describes the administration ofchromic tripicolinate for the treatment of adult-onset diabetes in dosesranging from 50 to 500 μg. U.S. Pat. No. 6,329,361, the entire contentsof which are hereby expressly incorporated herein by reference,discloses the use of high doses of chromic tripicolinate (providing1,000-10,000 μg chromium/day) for reducing hyperglycemia and stabilizingthe level of serum glucose in humans with Type 2 diabetes. U.S. Pat.Nos. 5,789,401 and 5,929,066, the entire contents of which are herebyexpressly incorporated herein by reference, disclose a chromictripicolinate-biotin composition and its use in lowering blood glucoselevels in humans with Type 2 diabetes.

U.S. Pat. Nos. 5,087,623; 5,087,624; and 5,175,156, the entire contentsof which are hereby expressly incorporated herein by reference, disclosethe use of chromium tripicolinate for supplementing dietary chromium,reducing hyperglycemia and stabilizing serum glucose, increasing leanbody mass and reducing body fat, and controlling serum lipid levels,including the lowering of undesirably high serum LDL-cholesterol levelsand the raising of serum High Density Lipid (HDL)-cholesterol levels.U.S. patent application Ser. Nos. 10/090,038 and 11/136,794, the entirecontents of which are hereby expressly incorporated by reference intheir entireties, disclose the use of high doses of chromium complexes(providing between 1,000 and 10,000 μg/day) and biotin for treatingdyslipidemia, and increasing serum HDL levels.

U.S. Pat. Nos. 4,954,492 and 5,194,615, the entire contents of which arehereby expressly incorporated by reference, describe a related complex,chromic nicotinate, which is also used for supplementing dietarychromium and lowering serum lipid levels. Picolinic acid and nicotinicacid are position isomers having the following structures:

Nicotinic acid and picolinic acid form coordination complexes withmonovalent, divalent and trivalent metal ions and facilitate theabsorption of these metals by transporting them across intestinal cellsand into the bloodstream and in some embodiments, nicotinic acid and/orpicolinic acid are incorporated into the outer coating of the tabletformulation to augment the efficacy of the combination therapy. In someembodiments, uncomplexed chelating agents are advantageously included inthe single dosage either with the nutritional supplement layer or as aseparate coating layer to facilitate absorption of other ingestedchromium as well as other metals including, but not limited to, copper,iron, magnesium, manganese, and zinc. Suitable chelating agents includehistidine, any essential amino D or L amino acids, tri amino acidformulae including but not limited to, triphenylalanine, tri histidine,tri arginine, picolinic acid, nicotinic acid, or both picolinic acid andnicotinic acid. Chelating agents such as histidine, picolinic acid andnicotinic acid are available from many commercial sources, includingSigma-Aldrich (St. Louis, Mo.) (picolinic acid; catalog No. P5503;nicotinic acid; catalog No. PN4126). Preferably, the ratio of thechromium complex to the chelating agent from about 10:1 to about 1:10(w/w), more preferably from about 5:1 to about 1:5 (w/w). Alternatively,the molar ratio of chromium complex to the uncomplexed chelating agentis preferably 1:1, and may be from about 5:1 to about 1:10. More thanone chelating agent, e.g, both nicotinic and picolinic acid can beincluded in the compositions disclosed herein, or administered tosubject in the methods described herein.

The amount of a compound of the invention that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques. As used herein, the term “treatment” or“treating” refers to an amelioration of a disease or disorder, or atleast one discernible symptom thereof. The term “treatment” or“treating” refers to inhibiting the progression of a disease ordisorder, either physically, e.g., stabilization of a discerniblesymptom, or physiologically, e.g., stabilization of a physicalparameter, or both.

In addition, in vitro or in vivo assays may optionally be employed tohelp identify optimal dosage ranges. The precise dose to be employed inthe compositions will also depend on the route of administration, andthe seriousness of the disease or disorder, and should be decidedaccording to the judgment of the practitioner and each circumstance.Suitable dosage ranges of metformin are well-established. Suitabledosage ranges for oral administration are generally about 0.001milligram to 5000 milligrams of a total chromium complex per kilogrambody weight. In preferred embodiments, the oral dose is 0.01 milligramtotal chromium complex to 1000 milligrams per kilogram body weight, morepreferably 0.1 milligram to 100 milligrams per kilogram body weight,more preferably 0.5 milligram to 25 milligrams per kilogram body weight,and yet more preferably 1 milligram to 10 milligrams per kilogram bodyweight. The dosage amounts described herein refer to total amountsadministered; that is, if more than one chromium complex or more thanone composition disclosed herein is administered, the preferred dosagescorrespond to the total amount of the compositions disclosed hereinadministered. Oral compositions preferably contain 10% to 95% activeingredient.

In accordance with the methods disclosed herein, the amount of chromiumprovided by the compositions that comprise chromium complexes disclosedherein can be at least 50 μg per day, for example at least 60 μg, atleast 70 μg, at least 80 μg, at least 90 μg, at least 100 μg, at least125 μg, at least 150 μg, at least 200 μg, at least 250 μg, at least 300μg, at least 350 μg, at least 400 μg, at least 450 μg, at least 500 μg,at least 550 μg, at least 600 μg, at least 650 μg, at least 700 μg, atleast 750 μg, at least 800 μg, at least 850 μg, at least 900 μg, atleast 950 μg, at least 1,000 μg, at least 1500 μg, at least 2,000 μg, atleast 2500 μg, at least 3000 μg, at least 3500 μg, at least 4000 μg, atleast 4500 μg or at least 5000 μg chromium complex/day. As discussedabove, chromium complexes may be trivalent complexes, such as chromiumpicolinate, chromic tripicolinate, chromium nicotinate, chromicpolynicotinate, chromium chloride, chromium histidinate, chromium yeast,or any other chromium complex, whether now known or to be developed inthe future.

By way of example, the level of chromium used for supplementation inorder to inhibit the onset of insulin resistance is at least about 50μg/day. Chromium picolinate and chromium chloride have been administeredto rats at levels several thousand times the upper limit of theestimated safe and adequate daily dietary intake (ESADDI) for chromiumfor humans (based on body weight) without toxic effects. R. Anderson etal., Lack of Toxicity of Chromium Chloride and Picolinate, 16 J. Am.Coll. Nutr. 273-279 (1997). While the level of chromium used forsupplementation may be within several thousand times the upper limit ofthe ESADDI, preferably, the amount of chromium is between about 50 and2,000 μg/day. More preferably, the amount of chromium is between about300 and 1,000 μg/day. Most preferably, the amount of chromium is betweenabout 400 and 1,000 μg/day. In a particularly preferred embodiment, theamount of chromium is between about 600 and 1,000 μg/day. These dosesare based on a 70 kg adult human, and that the dose can be applied on aper-kilogram basis to humans or animals of different weights.

In some embodiments, the amount of fast-acting chromium complex and theamount of slow acting chromium complex in a composition provide agreater than additive effect in lowering serum glucose levels thaneither complex alone. In some embodiments, the amount of fast-actingchromium complex and the amount of slow-acting chromium complex in acomposition provide a synergistic or greater than additive effect inimproving insulin sensitivity. In some embodiments, the amount offast-acting chromium complex and the amount of slow-acting chromiumcomplex in a composition provide a greater than additive effect intreating dyslipidemia. In some embodiments, the amount of fast-actingchromium complex and the amount of slow-acting chromium complex in acomposition provide a greater than additive effect in increasing leanmuscle mass.

In some embodiments, the compositions disclosed herein are provided inan amount effective for the prevention of insulin resistance. As usedherein, the term “insulin resistance (IR)” refers to a physiologicallyabnormal state in which cells do not respond appropriately to insulin,such that glucose in the blood cannot efficiently enter cells and,therefore, leads to hyperglycemia. Insulin resistance is believed toaffect one in three adult Americans which amounts to approximately 99.3million Americans with some degree of insulin resistance. Thecardiovascular and metabolic disturbances associated with IR canindividually and interdependently lead to a substantial increase incardiovascular disease (CVD) morbidity and mortality, making thecardiometabolic syndrome an established and strong risk factor forpremature and severe CVD and stroke. For example, in some embodiments, asubject is provided a single multiple unit dosage composition comprisingmetformin in combination with a sufficient amount of a chromium complexto inhibit or reduce the risk of the onset of insulin resistance. Theassessment of the affects of the compositions on insulin resistance canreadily be determined using routine techniques known to those skilled inthe art, and described, for example, in U.S. patent application Ser. No.10/090,038. The chromium complex may include chromium picolinate,chromic tripicolinate, chromium nicotinate, chromic polynicotinate,chromium chloride, chromium histidinate, chromium yeast, or otherchromium complex, whether now known or to be developed in the future.Effective doses of metformin are art-established. Effective doses ofchromium complex may be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems. Such animal models andsystems are well known in the art. Preferably, the sufficient amount ofchromium provided by the chromium complex and contained in thecomposition is between about 50 μg and 2000 μg.

Therapeutic Uses of Dosage Form Comprising a Therapeutic and aNutritional Supplement

In certain embodiments, the compounds and compositions disclosed hereincan be used as combination therapy with at least one therapeutic agentand at least one nutritional supplement. The nutritional supplement andthe therapeutic agent can act additively or, more preferably,synergistically. In one embodiment, a composition comprising, consistingessentially of, or consisting of an anti-diabetic agent with a chromiumcomplex is administered to an individual with diabetic nephropathy,diabetic retinopathy, a disorder of glucose metabolism, dyslipidemia,dyslipoproteinemia, insulin resistance, lipid elimination in bile,modulating C reactive protein, obesity, and/or metabolic syndromedisorders (e.g., Syndrome X) to improve glucose tolerance and/or laterlipid metabolism. As used herein, the term “improving glucose tolerance”indicates an observable (measurable) change in at least one aspect ofglucose metabolism, including but not limited to total blood glucosecontent, blood insulin, the blood insulin to blood glucose ratio,glycosylated hemoglobin, HOMAIR, beta cell function, composite ofinsulin sensitivity index, hyperglycemia, hyperglycemia, hypoglycemia,hormones, enhancing enzyme activities, improving hormonal balance causeddue to insulin resistance, abnormal glucose metabolism, lipodystrophy,reducing brain insulin resistance, insulin sensitivity, and oxygenconsumption. Abnormal glucose metabolism in conditions like polycysticovary syndrome, HIV, HIV lipodystrophy, Alzheimer's disease, mentalhealth disorders, lipodystrophy, hormonal imbalance conditions,hypertension, obesity and cardiovascular disease and cardiometabolicsyndrome. As used herein, the term “altering lipid metabolism” indicatesan observable (measurable) change in at least one aspect of lipidmetabolism, including but not limited to total blood lipid content,blood HDL cholesterol, blood LDL cholesterol, blood VLDL cholesterol,blood triglyceride, blood Lp(a), blood apo A-I, blood apo E and bloodnon-esterified fatty acids, esters of fatty acids, isomers, isoforms andratios and improving ratios for reducing chronic disease risk but notlimited to diabetes, obesity, hypertension, coronary heart disease andcardiovascular disease.

In another embodiment, a composition comprising, consisting essentiallyof, or consisting of an anti-inflammatory and a chromium complex areadministered to treat a thrombotic disorder, inflammatory bowel disease(e.g., Crohn's Disease, ulcerative colitis), arthritis (e.g., rheumatoidarthritis, osteoarthritis), autoimmune disease (e.g., systemic lupuserythematosus), scleroderma, ankylosing spondylitis, gout andpseudogout, muscle pain: polymyositis/polymyalgia rheumatica/fibrositis;infection and arthritis, juvenile rheumatoid arthritis, tendonitis,bursitis or other soft tissue rheumatism. Treatment or prevention ofinflammation is similarly contemplated and encompasses, but is notlimited to, chronic inflammatory disorders of the joints includingarthritis, e.g., rheumatoid arthritis and osteoarthritis; respiratorydistress syndrome, inflammatory bowel diseases such as ileitis,ulcerative colitis and Crohn's disease; and inflammatory lung disorderssuch as asthma and chronic obstructive airway disease, inflammatorydisorders of the eye such as corneal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis, and endophthalmitis;inflammatory disorders of the gum, e.g., periodontitis and gingivitis;tuberculosis; leprosy; inflammatory diseases of the kidney includingglomerulonephritis and nephrosis; inflammatory disorders of the skinincluding acne, sclerodermatitis, psoriasis, eczema, photoaging andwrinkles; inflammatory diseases of the central nervous system, includingAIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer'sdisease, encephalomyelitis and viral or autoimmune encephalitis;autoimmune diseases including immune-complex vasculitis, systemic lupusand erythematodes; systemic lupus erythematosus (SLE); and inflammatorydiseases of the heart such as cardiomyopathy.

“Insulin resistance” refers to a condition characterized by decreasedinsulin function and hyperinsulinemia, caused or exacerbated by drugsand disease conditions such to obesity, diabetes, CVD in a human orother animal. Examples of drugs which induce insulin resistance include,without limitation, statin drugs such as simvastatin, cerivastatin,pravastatin, atorvastatin, fluvastatin, and lovastatin; non-steroidalanti-inflammatory drugs such as cimicifuga, choline salicylate-magnesiumsalicylate, diclofenac sodium, diclofenac potassium, diflunisal,etodolac, fenoprofen calcium, floctafenine, flurbiprofen, ibuprofen,indomethacin, ketoprofen, ketorolac tromethamine, magnesium salicylate,mefenamic acid, nabumetone, naproxen, naproxen sodium, oxyphenbutazone,phenylbutazone, piroxicam, salsalate, sodium salicylate, sulindac,tenoxicam, taiprofenic acid, and tolmetin sodium; steroids such ashydrocortisone, dexamethasone, and methylprednisolone; contraceptivesincluding oral contraceptives such as estrogen, progesterone andprogestin as well as implantable contraceptives such as levonorgestrel,etonogestrel, nomegestrol acetate, and nestorone; hormone replacementtherapy (HRT) drugs including conjugated equine estrogens, esterifiedestrogens, estradiol, estrone, synthetic conjugated estrogens,estropipate, estropipate, ethinyl estradiol, norethindrone,medroxyprogesterone acetate, progestin, natural progesterone, tamoxifen,testosterone, and raloxifene; beta blocker drugs including acebutolol,atenolol, betaxolol, bucinodol, carteolol, labetalol, metoprolol,nadolol, penbutolol, pindolol, propanolol, and timolol; and diuretics.Three primary types of diuretics exist which include thiazides, loopdiuretics, and potassium sparing agents. As used herein, the term“diuretic” or “diuretics” includes, without limitation,hydrochlorothiazide, chlorthalidone, chlorothiazide, indapamide,metolazone, amiloride, spironolactone, triamterene, furosemide,bumetanide, ethacrynic acid, and torsemide. Certain immunosuppressivedrugs such as prednisolone, cyclosporin A, and tacromlimus and potassiumchannel modulators such as nicorandil are also included in thedefinition of drugs which induce insulin resistance, such as, forexample, antidepressants. The above list is provided for examplepurposes only and it is understood that the definition of “drug whichinduces insulin resistance” includes those drugs which induce insulinresistance that are not specifically listed above, as well as thosedrugs which are found to induce insulin resistance, whether in existencetoday or developed in the future. The co-formulation of a drug whichinduces insulin resistance with a nutritional supplement which treats orprevents insulin resistance such as chromium as a single tablet orcapsule reduces the likelihood of induction of insulin resistance. Bynot developing insulin resistance in the first place, the patient is notexposed to the associated diseases and risks.

Insulin resistance is a key pathogenic parameter of Type 2 diabetes, andclinical interventions that improve insulin sensitivity are consideredcornerstones in the management of the disease. In addition, therelationship of insulin resistance to cardiovascular disease and itsassociated risk factors has been well established over the past fewyears. Therefore, in a preferred embodiment, methods and compositionsfor thwarting the development of insulin resistance are providedcomprising the administration of a multiple unit dosage form having ahypoglycemic drug such as metformin, which inhibits insulin resistancefrom developing with a chromium complex. Combinations of pharmacologicagents (such as sulfonylureas/metformin, sulfonylureas/glitazones, andmetformin/glitazones) are highly effective pharmacologic interventionsthat appear to lower both glucose and insulin levels. Further, there isevidence that triple drug therapy (e.g.sulfonylureas/metformin/glitazones) can lower clinical glycemia inaddition to lowering insulin levels. Hence, in some embodiments,compositions comprising a chromium complex with metformin,sulfonylureas, and glitazones or combinations thereof are administeredto a subject taking drugs which induce insulin resistance to inhibit theonset of such insulin resistance.

The disclosure represents the present technology in that the subject hasa chance of developing insulin resistance or diabetes or associatedconditions but not limited to cardiovascular disease, obesity, diabetes,combination one or two disease conditions based on ATPIII guidelines andor due to mental health conditions such as depression, schizophrenia,Alzheimers disease and other conditions such HIV and HIV lipodystrophyand polycystic ovary syndrome. The insulin resistance might be due tofamily history, body weight, diet and drugs. The patient also does notneed to take additional, and sometimes costly, medications to treat theinsulin resistance and associated diseases.

Treatment of Cardiovascular Diseases

The present invention provides compositions and methods for thetreatment or prevention of a cardiovascular disease, comprisingadministering to a patient a therapeutically effective amount of acomposition comprising, consisting essentially of, or consisting of aconventional cardiovascular therapeutic and a nutritional supplementwith a pharmaceutically acceptable vehicle. As used herein, the term“cardiovascular diseases” refers to diseases of the heart andcirculatory system. These diseases are often associated withdyslipoproteinemias and/or dyslipidemias and/or familialhyperlipoproteinemias, hyper cholesterolemia and hyper lipidemia.Cardiovascular diseases which the compositions of the present inventionare useful for preventing or treating include but are not limited toarteriosclerosis; atherosclerosis; stroke; ischemia; endotheliumdysfunctions, in particular those dysfunctions affecting blood vesselelasticity; peripheral vascular disease; coronary heart disease;myocardial infarction; cerebral infarction and restenosis. Also includedare related pathologies, such as, for example, hypertrophy,hypertension, congestive heart failure, myocardial ischemia, ischemiareperfusion injuries in an organ, arrhythmia, and myocardial infarction.One embodiment is directed to a method of treating cardiovasculardisease in a mammal by concurrently administering to the mammal atherapeutically effective amount of a combination of warfarin as thetherapeutic agent component and magnesium taurate as the nutritionalsupplement component.

Treatment of Dyslipidemias

Also provided are compositions and methods for the treatment orprevention of a dyslipidemia comprising administering to a patient atherapeutically effective amount of a multiple unit dosage form having astatin drug and co-q10 and a pharmaceutically acceptable vehicle.

As used herein, the term “dyslipidemias” refers to disorders that leadto or are manifested by aberrant levels of circulating lipids. To theextent that levels of lipids in the blood are too high, the compositionsdescribed herein are administered to a patient to restore normal levels.Normal levels of lipids are reported in medical treatises known to thoseof skill in the art. For example, recommended blood levels of LDL, HDL,free triglycerides and others parameters relating to lipid metabolismcan be found at the web site of the American Heart Association and thatof the National Cholesterol Education Program of the National Heart,Lung and Blood Institute(http://www.americanheart.org/cholesterol/about_level.html andhttp://www.nhlbi.nih.gov/health/public/heart/chol/hbc_what.html,respectively). At the present time, the recommended level of HDLcholesterol in the blood is above 35 mg/dL; the recommended level of LDLcholesterol in the blood is below 70 mg/dL if they have multiple riskfactors; the recommended LDL:HDL cholesterol ratio in the blood is below5:1, ideally 3.5:1; and the recommended level of free triglycerides inthe blood is less than 200 mg/dL.

Dyslipidemias which the compositions of the present invention are usefulfor preventing or treating hyperlipidemia and low blood levels of highdensity lipoprotein (HDL) cholesterol. In certain embodiments, thehyperlipidemia for prevention or treatment by the compounds of thepresent invention is familial hypercholesterolemia; familial combinedhyperlipidemia; reduced or deficient lipoprotein lipase levels oractivity, including reductions or deficiencies resulting fromlipoprotein lipase mutations; hypertriglyceridemia;hypercholesterolemia; high blood levels of urea bodies (e.g. beta.-OHbutyric acid); high blood levels of Lp(a) cholesterol; high blood levelsof low density lipoprotein (LDL) cholesterol; high blood levels of verylow density lipoprotein (VLDL) cholesterol and high blood levels ofnon-esterified fatty acids.

The present invention further provides methods for altering lipidmetabolism in a patient, e.g., reducing LDL in the blood of a patient,reducing free triglycerides in the blood of a patient, increasing theratio of HDL to LDL in the blood of a patient, and inhibiting saponifiedand/or non-saponified fatty acid synthesis, said methods comprisingadministering to the patient a tablet, capsule, or other suitablevehicle for oral administration comprising an effective dose of a statindrug with an effective dose of co-Q10.

Treatment of Glucose Metabolism Disorders

Also provided are compositions and methods for the treatment orprevention of a glucose metabolism disorder, comprising providing to asubject with or at risk of developing a glucose metabolism disorder atherapeutically effective amount of a fast-acting chromium complex andslow-acting chromium complex and a pharmaceutically acceptable vehicle.As used herein, the term “glucose metabolism disorders” refers todisorders that lead to or are manifested by aberrant glucose storageand/or utilization. To the extent that indicia of glucose metabolism(i.e., blood insulin, blood glucose) are too high, the compositionsdescribed herein are administered to a patient to restore normal levels.Conversely, to the extent that indicia of glucose metabolism are toolow, the compositions described herein are administered to a patient torestore normal levels. Normal indicia of glucose metabolism are reportedin medical treatises known to those of skill in the art.

Glucose metabolism disorders which the compositions of the presentinvention are useful for preventing or treating include but are notlimited to impaired glucose tolerance; insulin resistance; insulinresistance related breast, colon or prostate cancer; diabetes, includingbut not limited to type 2 diabetes, type 1 diabetes, gestationaldiabetes mellitus (GDM), and maturity onset diabetes of the young(MODY); pancreatitis; hypertension; polycystic ovarian disease; HIVlipodystrophy, hormonal imbalance, hypercotisol levers, endothelialdysfunction, Alzheimers disease, aging and high levels of blood insulinand/or glucose.

Further provided are compositions and methods for altering glucosemetabolism in a patient, for example to increase insulin sensitivityand/or oxygen consumption of a patient, comprising administering to themammal an oral formulation comprising a therapeutic drug effective inaltering glucose metabolism and a chromium complex in an amounteffective to alter glucose metabolism.

Treatment of Cancer

Provided herein are compositions and methods for the treatment orprevention of cancer and related conditions. Cancer, including, but notlimited to, a tumor, metastasis, or any disease or disordercharacterized by uncontrolled cell growth, can be treated or preventedby combination therapy with a chemotherapeutic and nutritionalsupplementation as described herein. Cachexia, a condition related tocancer, is a systemic disease of which the cardinal symptoms areprogressive weight loss, anemia, edema, loss of appetite and so forth.It may occur as a side-effect of certain chronic diseases, such asmalignant tumors, tuberculosis, diabetes, blood diseases, endocrinediseases, infections and acquired immune deficiency syndrome. Whencachexia occurs as a result of the presence of a malignant tumor, evenif the administration of antitumor drugs to the patient with malignanttumor is effective and antitumor effects are experienced, there isnormally no improvement in the cachexia because of adverse effects suchas the myelotoxicity which may be caused by the antitumor drug. Sincethe strength of a patient is greatly depleted as cachexia progresses, itmay become impossible to continue treatment using antitumor drugs (whichgenerally exhibit a high level of toxicity), and this thereby becomes anobstacle to the treatment of the malignant tumor.

Nutritional supplements are often given in order to treat the symptomsof cachexia. This, however, often enhances the progress of the malignanttumor, and may shorten the survival time of the patient. The presentinvention provides a composition and method for treating cancer andrelated conditions. The method includes administering to a patient atherapeutically effective amount of a composition comprising achemotherapeutic agent as the therapeutic agent, a nutritionalsupplement, and a pharmaceutically acceptable vehicle. Types of cancerthat can be treated using combination chromium supplementation include,but are not limited to solid tumors, including but not limited tofibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenicsarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma,lymphangioendotheliosarcoma, synovioma mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer,kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovariancancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer,nasal cancer, throat cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomascystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma bile duct carcinoma choriocarcinoma seminoma,embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer,testicular cancer, small cell lung carcinoma, bladder carcinoma, lungcancer, epithelial carcinoma, glioma, glioblastoma multiformeastrocytoma medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma acoustic neuroma, oligodendroglioma, meningioma, skincancer, melanoma, neuroblastoma, retinoblastoma, Blood-borne cancers,including but not limited to: acute lymphoblastic B-cell leukemia, acutelymphoblastic T-cell leukemia, acute myeloblastic leukemia, “AML,” acutepromyelocytic leukemia “APL,” acute monoblastic leukemia, acuteerythroleukemic leukemia, acute megakaryoblastic leukemia, acutemyelomonocytic leukemia, acute nonlymphocyctic leukemia, acuteundifferentiated leukemia, chronic myelocytic leukemia, “CML,” chroniclymphocytic leukemia, “CLL,” hairy cell leukemia, multiple myeloma Acuteand chronic leukemias, Lymphoblastic myelogenous leukemias, lymphocyticmyelocytic leukemias, Lymphomas: such as Hodgkin's disease,non-Hodgkin's Lymphoma, Multiple myeloma, Waldenstrom'smacroglobulinemia, Heavy chain disease, and Polycythemia vera.

The chemotherapeutic agent can be at least one of paclitaxel,doxorubicin, and/or other drugs which have been known to affect tumors.Chemotherapeutics, as used herein, further includes agents whichmodulate other states which are related to tissues which can bepermeabilized using the methods and compositions of the invention. Thechemotherapeutic agent can be, for example, a steroid, an antibiotic, oranother pharmaceutical composition. Examples of chemotherapeutic agentsinclude agents such as paclitaxel, doxorubicin, vincristine,vinblastine, vindesine, vinorelbin, taxotere (DOCETAXEL), topotecan,camptothecin, irinotecan hydrochloride (CAMPTOSAR), doxorubicin,etoposide, mitoxantrone, daunorubicin, idarubicin, teniposide,amsacrine, epirubicin, merbarone, piroxantrone hydrochloride,5-fluorouracil, methotrexate, 6-mercaptopurine, 6-thioguanine,fludarabine phosphate, cytarabine (ARA-C), trimetrexate, gemcitabine,acivicin, alanosine, pyrazofurin, N-Phosphoracetyl-L-Asparate (PALA),pentostatin, 5-azacitidine, 5-Aza-2′-deoxycytidine, adenosinearabinoside (ARA-A), cladribine, ftorafur, UFT (combination of uraciland ftorafur), 5-fluoro-2′-deoxyuridine, 5-fluorouridine,5′-deoxy-5-fluorouridine, hydroxyurea, dihydrolenchlorambucil,tiazofurin, cisplatin, carboplatin, oxaliplatin, mitomycin C, BCNU(Carmustine), melphalan, thiotepa, busulfan, chlorambucil, plicamycin,dacarbazine, ifosfamide phosphate, cyclophosphamide, nitrogen mustard,uracil mustard, pipobroman, 4-ipomeanol, dihydrolenperone, spiromustine,geldanamycin, cytochalasins, depsipeptide, Lupron, ketoconazole,tamoxifen, goserelin (Zoledax), flutamide,4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluorometh-yl)propionanilide,Herceptin, anti-CD20 (Rituxan), interferon alpha, interferon beta,interferon gamma, interleukin 2, interleukin 4, interleukin 12, tumornecrosis factors, and radiation. Representative compounds used in cancertherapy further include cyclophosphamide, chlorambucil, melphalan,estramustine, iphosphamide, prednimustin, busulphan, tiottepa,carmustin, lomustine, methotrexate, azathioprine, mercaptopurine,thioguanine, cytarabine, fluorouracil, vinblastine, vincristine,vindesine, etoposide, teniposide, dactinomucin, doxorubin, dunorubicine,epirubicine, bleomycin, nitomycin, cisplatin, carboplatin, procarbazine,amacrine, mitoxantron, tamoxifen, nilutamid, and aminoglutemide.

The nutritional supplement component of the formulation can be any of avitamin, mineral, essential fatty acid or fatty alcohol, essentialmetal, or botanical as described above which compensates for nutritionaldeficiencies associated with cancer treatment or which augments theactivity of the chemotherapeutic agent.

Treatment of Other Diseases

Also provided herein are compositions and methods for the treatment orprevention of schizophrenia comprising administering to a patient atherapeutically effective amount of a multiple unit dosage formcomprising, consisting essentially of, or consisting of ananti-psychotic such as olanzapine and a chromium complex, and apharmaceutically acceptable vehicle.

The invention described herein further includes a composition and methodfor treating depression. The method includes identifying a subjectsuffering from depression and administering to said subject atherapeutically effective dose of a multiple unit oral formulationcomprising an anti-depressant such as sertraline and a nutrient such aschromium, wherein the combination therapy results in a reduction in thesymptoms of depression.

In addition to treating or preventing obesity, the compositionsdescribed herein can be administered to an individual to promote weightreduction of the individual. Conventional weight loss therapeutics canbe formulated with a nutritional supplement coating to compensate forany nutritional depletion associated with weight loss treatment.

Veterinary and Livestock Uses

Compositions described herein can be administered to an animal ornon-human animal for a veterinary use for treating or preventing adisease or disorder disclosed herein.

In a specific embodiment, the non-human animal is a household pet. Inanother specific embodiment, the non-human animal is a livestock animal.In a preferred embodiment, the non-human animal is a mammal, mostpreferably a cow, horse, sheep, pig, cat, dog, mouse, rat, rabbit, orguinea pig. In another preferred embodiment, the non-human animal is afowl species, most preferably a chicken, turkey, duck, goose, or quail.

In addition to veterinary uses, the compositions disclosed herein can beused to reduce the fat content of livestock to produce leaner meats.Alternatively, the compositions disclosed herein can be used to reducethe cholesterol content of eggs by administering the compounds to achicken, quail, or duck hen. For non-human animal uses, the compositionsdisclosed herein can be administered via the animals' feed or orally asa drench composition.

Therapeutic/Prophylactic Administration and Compositions

Due to the activity of the compounds and compositions described herein,they are useful in veterinary and human medicine. As described above,the compounds and compositions described herein are useful for thetreatment or prevention of cardiometabolic syndrome, aging, Alzheimer'sDisease, cancer, cardiovascular disease, diabetic nephropathy, diabeticretinopathy, a disorder of glucose metabolism, dyslipidemia,dyslipoproteinemia, hypertension, impotence, inflammation, insulinresistance, lipid elimination in bile, modulating C reactive protein,obesity, oxysterol elimination in bile, pancreatitis, Parkinson'sdisease, a peroxisome proliferator activated receptor-associateddisorder, phospholipid elimination in bile, renal disease, septicemia,metabolic syndrome disorders (e.g., Syndrome X), a thrombotic disorder,enhancing bile production, -enhancing reverse lipid transport,inflammatory processes and diseases like gastrointestinal disease,irritable bowel syndrome (IBS), inflammatory bowel disease (e.g.,Crohn's Disease, ulcerative colitis), arthritis (e.g., rheumatoidarthritis, osteoarthritis), autoimmune disease (e.g., systemic lupuserythematosus), scleroderma, ankylosing spondylitis, gout andpseudogout, muscle pain: polymyositis/polymyalgia rheumatica/fibrositis;infection and arthritis, juvenile rheumatoid arthritis, tendonitis,bursitis and other soft tissue rheumatism.

Provided herein are methods of treatment and prophylaxis of theconditions enumerated above by providing to a subject of a multiple unitdosage form having a therapeutically effective amount of a therapeuticagent and a nutritional supplement as disclosed herein. The mammal is ananimal, including, but not limited, to an animal such a cow, horse,sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guineapig, etc., and most preferably a human.

The compositions disclosed herein are useful for methods for treatingdiabetes and its related pathologies, cardiovascular and relateddiseases, such as, for example, diabetes retinopathy, diabetesnephropathy, diabetes neuropathy, diabetes foot problems, diabetesinfections and inflammations, diabetes with cardiovascular complicationssuch as hypertrophy, hypertension, congestive heart failure, myocardialischemia, ischemia reperfusion injuries in an organ, arrhythmia, andmyocardial infarction. One embodiment is directed to a method oftreating cardiovascular disease in a mammal by concurrentlyadministering to the mammal a therapeutically effective amount of acombination of a compound suitable for use in methods described hereinand a therapeutic cardiovascular compound such as chromium histidine orchromium complex as a multiple unit dosage form.

Other methods will be known to the skilled artisan and are within thescope described herein, including processes for preparing theformulations described above.

The foregoing description details certain embodiments of the invention.It will be appreciated, however, that no matter how detailed theforegoing appears in text, the invention can be practiced in many ways.As is also stated above, it should be noted that the use of particularterminology when describing certain features or aspects of the inventionshould not be taken to imply that the terminology is being re-definedherein to be restricted to including any specific characteristics of thefeatures or aspects of the invention with which that terminology isassociated. The scope of the invention should therefore be construed inaccordance with the appended claims and any equivalents thereof.

1. A multiple unit dosage form for oral administration comprising aneffective amount of a therapeutic agent, a barrier layer, and anutritional supplement, wherein said therapeutic agent and saidnutritional supplement are formulated as a single dose.
 2. The dosageform of claim 1, wherein said barrier layer is located between thetherapeutic agent and said nutritional supplement and preventsinteraction between said therapeutic agent and said nutritionalsupplement.
 3. The dosage form of claim 1, wherein said barrier layer iscomprised of a controlled-release, delayed-release, or enteric coating.4. The dosage form of claim 1, wherein said therapeutic agent is locatedat the center of the form and the nutritional supplement is located atthe outer portion of the form, and wherein the barrier layer separatesthe therapeutic agent from the nutritional supplement.
 5. The dosageform of claim 1, wherein said nutritional supplement is located at thecenter of the form and the therapeutic agent is located at the outerportion of the form, and wherein the barrier layer separates thenutritional supplement from the therapeutic agent.
 6. The dosage form ofclaim 1, wherein said therapeutic agent is selected from the groupconsisting of an antidepressant, an anti-thombotic, an anti-diabetic, ananti-psychotic, and a statin drug.
 7. The dosage form of claim 1,wherein said nutritional supplement is selected from the groupconsisting of a vitamin, a mineral, an essential metal, and a co-enzyme.8. The dosage form of claim 1, wherein said nutritional supplement is achromium complex selected from the group consisting of chromiumpolynicotinate, chromium picolinate, chromium acetate, chromiumhistidinate, chromium nicotinate, chromium chloride, and chromium yeast.9. The dosage form of claim 8, wherein said therapeutic is olanzapine.10. The dosage form of claim 8, wherein said therapeutic is metformin.11. The dosage form of claim 8, wherein said therapeutic is sertraline.12. The dosage form of claim 8, wherein said therapeutic is tamoxifen.13. The dosage form of claim 8, wherein said therapeutic is insulin. 14.The dosage form of claim 1, wherein said nutritional supplement is folicacid and said therapeutic is selected from the group consisting of anoral contraceptive, an H2 receptor antagonist, a non-steroidalanti-inflammatory drug, and metformin.
 15. The dosage form of claim 1,wherein said nutritional supplement is zinc, and wherein saidtherapeutic is an angiotensin converting enzyme inhibitor (ACEinhibitor).
 16. The dosage form of claim 1, wherein said nutritionalsupplement is vitamin B12 and said therapeutic is selected from thegroup consisting of metformin and a proton pump inhibitor.
 17. Thedosage form of claim 1, wherein said nutritional supplement is iron, andwherein said therapeutic is an H2 receptor antagonist.
 18. The dosageform of claim 1, wherein said nutritional supplement is selenium, andwherein said therapeutic is an HIV therapeutic.
 19. The dosage form ofclaim 1, wherein said nutritional supplement is carnitine, and whereinsaid therapeutic is an HIV therapeutic.
 20. The dosage form of claim 1,wherein said therapeutic is a statin, and wherein said nutritionalsupplement is selected from the group consisting of chromium, niacin,and Co-enzyme Q10.
 21. The dosage form of claim 1, wherein saidtherapeutic is a prostate cancer therapeutic and said nutritionalsupplement is selenium.
 22. A method of preventing and/or attenuatingdepletion of a nutrient caused by the co-administration of a therapeuticagent to an individual in need thereof, comprising: identifying anindividual presenting with nutrient depletion associated with theadministration of a therapeutic agent, administering to said individualthe dosage form of claim 1, wherein said therapeutic agent causes orexacerbates nutrient depletion and wherein said nutritional supplementprevents and/or attenuates said depletion.
 23. A method ofsynergistically treating a disease or condition caused or exacerbated bynutrient depletion comprising administering to an individual in needthereof the dosage form of claim 1.